Catalytic Mechanisms of Fe(II)- and 2-Oxoglutarate-dependent Oxygenases

Martinez, Salette; Hausinger, Robert P.

doi:10.1074/jbc.r115.648691

Cited by 365 publications

(477 citation statements)

References 86 publications

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“…We also determined the cofactor complex structure of KDM5A-αKG-Mn(II) to a higher resolution at 1.39 Å (Figure 3A). Like other structurally characterized αKG-dependent dioxygenases (Martinez and Hausinger, 2015), the metal ion was bound by six ligands in an octahedral coordination. The side chains of His-483, Glu-485, and His-571 (i.e.…”

Section: Resultsmentioning

confidence: 94%

Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds

Horton

Liu

Gale

et al. 2016

Cell Chemical Biology

105

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SUMMARY The KDM5/JARID1 family of Fe(II)- and α-ketoglutarate-dependent demethylases removes methyl groups from methylated lysine 4 of histone H3. Accumulating evidence supports a role for KDM5 family members as oncogenic drivers. We compare the in vitro inhibitory properties and binding affinity of ten diverse compounds with all four family members, and present the crystal structures of the KDM5A linked Jumonji domain in complex with eight of these inhibitors in the presence of Mn(II). All eight inhibitors structurally examined occupy the binding site of α-ketoglutarate, but differ in their specific binding interactions, including the number of ligands involved in metal coordination. We also observed inhibitor-induced conformational changes in KDM5A, particularly those residues involved in the binding of α-ketoglutarate, the anticipated peptide substrate, and intra-molecular interactions. We discuss how particular chemical moieties contribute to inhibitor potency and suggest strategies that might be utilized in the successful design of selective and potent epigenetic inhibitors.

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Section: Resultsmentioning

confidence: 94%

Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds

Horton

Liu

Gale

et al. 2016

Cell Chemical Biology

105

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“…. H (68). The ␣-ketoglutarate and its non-reactive analog N-oxalylglycine are bound with a dissociation constant (K D ) of ϳ80 and 47 M, respectively, measured by isothermal titration calorimetry (Fig.…”

Section: Deletion Of ⌬Ap Has No Effect On Kinetics Of Kdm5c-mentioning

confidence: 99%

Characterization of a Linked Jumonji Domain of the KDM5/JARID1 Family of Histone H3 Lysine 4 Demethylases

Horton¹,

Engstrom²,

Zoeller³

et al. 2016

Journal of Biological Chemistry

104

165

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The KDM5/JARID1 family of Fe(II)-and ␣-ketoglutarate-dependent demethylases remove methyl groups from tri-and dimethylated lysine 4 of histone H3. Accumulating evidence from primary tumors and model systems supports a role for KDM5A (JARID1A/RBP2) and KDM5B (JARID1B/PLU1) as oncogenic drivers. The KDM5 family is unique among the Jumonji domain-containing histone demethylases in that there is an atypical insertion of a DNA-binding ARID domain and a histone-binding PHD domain into the Jumonji domain, which separates the catalytic domain into two fragments (JmjN and JmjC). Here we demonstrate that internal deletion of the ARID and PHD1 domains has a negligible effect on in vitro enzymatic kinetics of the KDM5 family of enzymes. We present a crystal structure of the linked JmjN-JmjC domain from KDM5A, which reveals that the linked domain fully reconstitutes the cofactor (metal ion and ␣-ketoglutarate) binding characteristics of other structurally characterized Jumonji domain demethylases. Docking studies with GSK-J1, a selective inhibitor of the KDM6/ KDM5 subfamilies, identify critical residues for binding of the inhibitor to the reconstituted KDM5 Jumonji domain. Further, we found that GSK-J1 inhibited the demethylase activity of KDM5C with 8.5-fold increased potency compared with that of KDM5B at 1 mM ␣-ketoglutarate. In contrast, JIB-04 (a paninhibitor of the Jumonji demethylase superfamily) had the opposite effect and was ϳ8-fold more potent against KDM5B than against KDM5C. Interestingly, the relative selectivity of JIB-04 toward KDM5B over KDM5C in vitro translates to a ϳ10 -50-fold greater growth-inhibitory activity against breast cancer cell lines. These data define the minimal requirements for enzymatic activity of the KDM5 family to be the linked JmjNJmjC domain coupled with the immediate C-terminal helical zinc-binding domain and provide structural characterization of the linked JmjN-JmjC domain for the KDM5 family, which should prove useful in the design of KDM5 demethylase inhibitors with improved potency and selectivity.

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“…Generally, these functions are related to the JmjC/cupin-like dioxygenase domain that is the hallmark of this protein family. Published activities of various JmjC proteins include demethylation of lysines in histones, demethylation of RNA and DNA, and hydroxylation of various amino acids (6,8,9). While many members of the JmjC protein family have been characterized biochemically, the functions of several members, including JMJD4-JMJD8 and HSPBAP1 remain uncharacterized or controversial.…”

mentioning

confidence: 99%

“…Interestingly, proteins of the JmjC domain family have been reported to possess diverse enzymatic activities (6)(7)(8). Generally, these functions are related to the JmjC/cupin-like dioxygenase domain that is the hallmark of this protein family.…”

mentioning

confidence: 99%

Clipping of arginine-methylated histone tails by JMJD5 and JMJD7

Liu

Wang

Lee

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Two of the unsolved, important questions about epigenetics are: do histone arginine demethylases exist, and is the removal of histone tails by proteolysis a major epigenetic modification process? Here, we report that two orphan Jumonji C domain (JmjC)-containing proteins, JMJD5 and JMJD7, have divalent cationdependent protease activities that preferentially cleave the tails of histones 2, 3, or 4 containing methylated arginines. After the initial specific cleavage, JMJD5 and JMJD7, acting as aminopeptidases, progressively digest the C-terminal products. JMJD5-deficient fibroblasts exhibit dramatically increased levels of methylated arginines and histones. Furthermore, depletion of JMJD7 in breast cancer cells greatly decreases cell proliferation. The protease activities of JMJD5 and JMJD7 represent a mechanism for removal of histone tails bearing methylated arginine residues and define a potential mechanism of transcription regulation.histone tail | arginine methylation | clipping | JMJD5/7

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Catalytic Mechanisms of Fe(II)- and 2-Oxoglutarate-dependent Oxygenases

Cited by 365 publications

References 86 publications

Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds

Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds

Characterization of a Linked Jumonji Domain of the KDM5/JARID1 Family of Histone H3 Lysine 4 Demethylases

Clipping of arginine-methylated histone tails by JMJD5 and JMJD7

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